Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors

Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme. Here, based on those findings, we describe further chemical modifications of the protruding subset of GEBR library inhibitors and their effects on ligand conformation and potency. In particular, we demonstrate that the insertion of a methyl group in the flexible linker region connecting the catechol portion and the basic end of the molecules enhances the ability of the ligand to interact with both the catalytic and the regulatory domains of the enzyme. [Display omitted] •New members of GEBR library, characterized by methylated or constrained linker chain, have been designed and synthesized.•Open chain derivatives show stronger PDE4D inhibition than the corresponding analogues lacking the methyl substituent.•On the contrary, constrained compounds show very low PDE4D inhibition.•Crystallography reveal that the methyl group points toward the bottom of the catalytic pocket increasing the binding force.•Chain flexibility is necessary in order to facilitate the interaction of the ligands with catalytic and regulatory domains.